WO2008120966A1 - Pharmaceutical composition in the form of a sublingual tablet consisting of a non-steroidal anti-inflammatory agent and an opiate analgesic for pain management - Google Patents

Abstract

The invention relates to a pharmaceutical composition consisting of a combination of two active ingredients, one of said active ingredients being a non-steroidal anti-inflammatory agent, known as ketorolac, and the other being an opiate analgesic known as tramadol. Said agents are formulated in the form of an orally administered sublingual tablet used to relieve and/or treat moderately or severely intense pain. The combination of said pharmaceuticals generates a stronger analgesic effect, greater bioavailability and a faster speed of action using smaller dosages, with less collateral effects.

Description

 PHARMACEUTICAL COMPOSITION IN THE FORM OF A SUBLINGUAL TABLET THAT INCLUDES A NON-STEROID ANTI-INFLAMMATORY AND AN OPIACEAL ANALGESIC FOR THE MANAGEMENT

PAIN.

FIELD OF THE INVENTION

The present invention has application in the pharmaceutical industry and relates to the development of a pharmaceutical composition composed of the synergistic association or combination of a non-steroidal anti-inflammatory agent, known as: Ketorolac tromethamine and an opioid analgesic agent, known as: Tramadol hydrochloride, which are formulated in a single dosage unit in the form of a sublingual tablet and is indicated in patients with moderate to severe pain.

The combination of these active principles when administered together in a single dosage unit produces an analgesic synergy that results in a greater analgesic effect unlike when these active principles are administered independently, providing benefits such as: lower dosages, avoid side effects that may occur when doses of the active ingredients are administered independently by other routes of administration, in addition to avoiding a first-pass metabolism.

BACKGROUND OF THE INVENTION

Pain is one of the main and major causes of medical consultation in patients of all ages; For this reason, it is important to know the behavior and variations that this symptom presents. Commonly, patients expect the manifestation of pain to be too severe or intolerable to see a professional. Pain may be a symptom or the consequence of an injury, illness or surgery. There are many definitions that attempt to conceptualize the meaning of pain, one of these definitions says that: it is the sensory perception of an unpleasant sensation associated with the emotional experience produced by current or potential tissue damage.

The perception and experience of pain manifested by a patient are affected by many factors, among which are: its causes, the basis patient cultures, as well as previous experiences and emotions; being these factors those that motivate that the threshold and the tolerance are variable in the different people and even in the same individual in different circumstances.

The definition described above fully amplifies that belief that pain was simply an unpleasant nerve impulse and replaces it with the concept of experience, that is, an integration of all previous and current conditions before a nociceptive stimulus (nociception: noxa reception or damage ). At the moment of pain, the patient integrates his previous experiences before similar stimuli, consciously processes them and nuances them with the affective tone (always variable, depending on the circumstance in which the nociceptive episode occurs).

Perception is definitely not pleasant and either sensory (pure nociception), or emotional (ranging from a simple affective component in perception to the very generation of painful perception by purely psychogenic mechanisms) is unpleasant and always tends to be described in sensory terms, of tissue destruction, of painful intensity, of affection and / or evaluation.

The pain is classified as: Acute Pain, which is of recent onset with cause usually demonstrable, but not always, and may persist for minutes to days. Pain lasting more than 72 hours is called: Subagudo. It is considered as Chronic Pain that lasts more than three months, but this limit is quite arbitrary, since it can be suffered for several months and even for years, although its definition and causes are varied.

The pain may have as a reference a site distant from its origin and is common in conditions of internal organs or viscera such as kidneys, colon, uterus and rectum that can refer to the lumbosacral region. The anatomical basis of the referred pain is the somatic and visceral tissues that are innervated by afferent fibers of the same segment of the spinal root. The primary nociceptive pathways interconnect with other spinal segments and thus their perception can be located in a place distant from the site of the actual disease. The nociceptive stimulus can produce hyperexcitability in nerve cells of the spinal cord that can refer pain to related tissues. The pain can radiate from its site of origin and produce a large painful area. The perception of pain begins with the stimulation of the primary receptors found in the skin or deep tissues. The two types of nociceptors, A-delta and C fibers can respond to thermal stimuli, chemical signals or mechanical deformation. The number and type of pain receptors varies in the various tissues, - for example, the ligaments and periosteum, are richly innervated by them, for this reason, the lesions in these areas are quite painful; on the other hand, normal articular cartilage has no pain receptors, with the possibility that it will be severely injured without any manifestation of pain. The visceral pleura also has no pain receptors, which would explain that disseminated diseases in the abdomen may be not very painful. When the tissue is injured, various chemicals such as histamines, prostaglandins and bradykidines are released, which not only They stimulate the pain receptor, but also make it hypersensitive for future stimuli.

Once damage or injury occurs, the affected area becomes particularly sensitive and irritable and the resulting ischemia subsequently in damaged tissues causes pain from the release of these chemicals that, when they affect nerve cells, from damage to the vessels blood, the cause of peripheral neuropathies is considered, as in the diabetic. The primary pain receptor communicates with the spinal cord through each nerve root and synapses with other neurons before the painful stimulus rises to higher centers, such as the thalamus and / or the brain. The interpretation of the painful stimulus can be modified in the spinal cord. This is the basis of the operation of some treatments such as transcutaneous electrical stimulation (TENS) and other sensory counter-stimulation techniques. In centers such as the thalamus, brain and spinal cord, changes in the appearance of pain can also occur through descending inhibitory pathways. The brain and spinal cord produce opioids Endogenous, such as: encephali and endorphins that reduce pain perception. Damage to nerve tissue, both peripheral and central, or both, can cause neurogenic pain. Experimental studies indicate that in the absence of disease, there is no relative age to differentiate perception and tolerance to pain; However, this should be interpreted with caution, because the change in the perception of pain in the different individuals during the course of their life has not been well studied and these studies do not include very elderly patients (85 or older ), which is the age range in which many diseases and more constant manifestations of pain are expected to suffer. Chronic pain has narrow psychological, emotional and sociological components, as it has been shown that there is a strong relationship between pain, depression and anxiety in groups of all ages. This relationship is complex, interactive and poorly understood. The long-term effects, on the physical, psychological and social well-being of an individual, make a chronically sore person more prone to depression, especially if he is older. Likewise, a depressed patient may take longer to recover and that may alter his experience of pain. Other factors associated with pain and depression are high levels of deconditioning or physical limitations.

Painful diseases are of greater interest in older adults than in young people, since older adults are more exposed to conditions that cause the manifestation of pain of both types: acute and chronic. Surgical procedures are performed more frequently in older adults because they are more predisposed to have long-standing diseases associated with significant pain, such as: osteoarthritis, osteoporosis with vertebral fractures, diabetes with peripheral neuropathy, cancer, peripheral vascular disease, postherpetic neuropathy, etc.

Currently there is a wide variety of pharmaceutical products useful for the treatment of pain, - however, in these medications the active ingredients are administered independently causing the relief of the condition is slower and less effective. Ketorolac is a non-steroidal anti-inflammatory agent that has analgesic, anti-inflammatory and antipyretic properties; which has been used in patients with pain, and can be administered orally, intramuscularly or intravenously. This active substance inhibits the synthesis of prostaglandins and is a potential analgesic with peripheral activity. It has moderate anti-inflammatory effect. Ketorolac has been shown to show greater analgesic efficiency compared to the effect manifested by opioids (according to clinical studies reported by Yee, et al in 1986; O'Hara, et al in 1987; Forbes, et al in 1990 ). The analgesic activity of Ketorolac 30 mg is equivalent to 9 mg of Morphine, but without it causing adverse effects such as: drowsiness, nausea, vomiting and no breathing effects. The analgesic effect of 10 to 20 mg. of Ketorolac administered orally is equivalent to 650 mg. of Acetylsalicylic Acid or 600 mg. of Acetaminophen with 60 mg. of Codeine. Unlike opioids, ketorolac does not decrease the CAM of inhaled anesthetics. When administering clinical doses of Ketorolac, there are no manifestations of cardiovascular or respiratory effects. Ketorolac inhibits platelet aggregation, an inhibition that disappears within 24 to 40 hours. after withdrawing the medication, without altering the platelet count, prothrombin time or partial thromboplastin time.

Ketorolac has been shown to be effective for the short-term treatment of pain of moderate to severe intensity Bloomfield et al 1986), caused by various etiologies, mainly in clinical settings where a strong and sustained analgesic activity is necessary, without presenting the adverse effects manifested by the administration of opioid analgesics. It is indicated for the treatment of pain: post-surgical, traumatological, orthopedic, rheumatological, gynecological, urological, neurological, oncological, dental and renal and biliary colic. Ketorolac intervenes peripherally in the biochemical mechanisms that cause the painful sensation, blocking the uptake and spread of pain to the medullary nerve centers and brain The intensity of pain is quickly relieved or totally eliminated.

Ketorolac acts by inhibiting the enzyme cyclooxygenase, with inhibition of peripheral synthesis of prostaglandins, which are involved in the inflammatory and painful process, reducing pain and inflammation. The analgesic effect is basically peripheral, not altering the pain threshold. Its anti-thermal action is exerted by inhibition of prostaglandins that mediate the effects of endogenous pyrogens at the hypothalamic level. In addition, it induces the decrease in cytoprotection of the gastric mucosa, the decrease in renal blood flow, as well as the inhibition of platelet aggregation. It has discreet anticholinergic and α-blocking activity. It is absorbed quickly and completely, reaching its maximum plasma concentrations between 30 and 60 minutes after administration. After intramuscular and oral administration, its analgesic effect begins at 10 and 30 minutes, respectively, lasting 6 to 8 hours. , in both cases . Ketorolac crosses the placenta and is secreted by breast milk. Has a plasma half-life from 3.5 to 8.6 hours. It is metabolized in the liver and about 91% of the dose is eliminated in the urine without changes, the rest is excreted in the stool. Tramadol is a centrally acting opioid analgesic (narcotic). It is a weak μ opioid receptor agonist that has noradrenergic properties, inhibiting norepinephrine reuptake; and serotonergic, inhibiting the release of serotonin in nerve endings, which contribute to its analgesic activity.

Tramadol has been used in Europe since the 70's and in the United States since the late 80's to relieve many types of painful conditions. Tramadol is used for pain relief of moderate to severe intensity and acts on specific nerve cells of the spinal cord and brain, which decrease the intensity of pain sensation, a natural function that is increased by administering this drug. .

Tramadol can be administered orally, intramuscularly or intravenously. Concentrations Maximum plasma levels are reached between 1.5 and 2 hrs. After oral administration, it has a bioavailability of 79%. It is metabolized in the liver producing active metabolites such as Ml. The half-life of the analgesic effect of Tramadol is approximately 6 hours after the administration of each dose and the onset of the analgesic effect is manifested after 10 to 20 min. after administration, being mostly eliminated in the urine.

Tramadol is used to treat manifestations of pain caused by: (post-operative) surgery, joint trauma (post-traumatic), chronic conditions such as cancer, neuropathic pain, among others, - and works by decreasing the body's sensitivity to such manifestations of pain

At present, there is a wide variety of medications for the treatment of pain, which are administered orally in solid form. The pharmaceutical composition object of the present invention is formulated in a single unit of dosage in the form of a sublingual tablet to be administered orally.

Sublingual tablets are designed to dissolve rapidly in oral fluids, thereby obtaining greater speed and rapidity in the absorption of the active ingredients contained in the pharmaceutical composition. The mechanism of disintegration of these medications is carried out by dissolving them under the tongue or between the gums and cheek so that a rapid absorption of the active substances is carried out and they reach the bloodstream in a period of time as short as possible. If these pharmaceutical compositions in the form of a sublingual tablet become swallowed or swallowed, their therapeutic effect turns out to be ineffective or less effective with respect to the effect obtained when properly administered.

SUMMARY OF THE INVENTION The objective of the present invention is focused on the development of a pharmaceutical composition composed of the synergistic combination of a non-steroidal anti-inflammatory agent with analgesic activity, known as: Ketorolac and an agent opioid analgesic, such as: Tramadol, which are formulated in a single dosage unit to be administered orally in the form of a sublingual tablet, which provides benefits such as: lower dosage of the active ingredients, faster the absorption of the active ingredients and avoids the manifestation of adverse effects that commonly occur when administering the active substances independently and in larger doses. DETAILED DESCRIPTION OF THE INVENTION.

Historically, the fact of associating or combining active ingredients that have similar or different therapeutic activity applied to pain management has been a matter of controversy. The technical basis that justifies this clinical practice is easy to state. Anti-inflammatories are drugs that base their analgesic power on their ability to inhibit prostaglandins and thereby reduce inflammation; while the central analgesics, when interacting with their specific receptors, produce an alteration of the permeability of the neuronal membrane in such a way that selectively inhibit the nociceptive impulse, being therefore pure analgesics.

In recent years there has been a very important trend for the research and development of pharmaceutical compositions composed of the combination of active ingredients with specific analgesic activity, formulated in a single dose unit, with the aim of achieving an analgesic synergy in which lower doses of the active substances are used and that this results in a reduction of the adverse effects manifested unlike when said active ingredients are administered independently and in larger doses. On the other hand, an important emphasis has been generated in the development of new pharmaceutical forms that increase the speed of absorption of the formulated active principles, and also increase their bioavailability and therapeutic efficacy, with lower risks of side effects being manifested.

The development of the present invention is based on the synergistic combination of a non-steroidal anti-inflammatory agent, known as: Ketorolac and an opioid analgesic agent, such as: Tramadol, which are formulated in a single dosage unit to be administered orally as a sublingual tablet, indicated for the treatment of pain with moderate to severe intensity.

Ketorolac manifests itself as a non-steroidal anti-inflammatory drug (NSAID) with classic characteristics, that is, with high anti-inflammatory power and therefore marked analgesic action. Tramadol, on the other hand, is not shown as a typical central analgesic, since its central action is associated with its ability to inhibit the reuptake of norepinephrine and 5-hydroxytryptamine, thus giving a novel profile to the pharmaceutical composition of the present invention, in terms of its effective analgesic power, staying within safety margins not known until today in central analgesics. From the association of these two active principles with different mechanisms of action, which were formulated in the form of a sublingual tablet, quite satisfactory results were obtained, which are described below. We began our investigations by conducting preclinical studies that in the first instance demonstrated the synergy of the combination.

Example 1: For the purpose of determining the possibility of a synergistic antinociceptive interaction, the antinociceptive effects of Ketorolac tromethamine, p.o., a non-steroidal anti-inflammatory drug were determined

(NSAID) and Tramadol Hydrochloride, po, an atypical analgesic opioid, administered both separately and in combination. For this purpose, a model of arthritic pain in rats was determined. The data were interpreted using the Synergic Surface Interaction Analysis (ISS) and an Isobolographic Analysis to determine the nature of the interaction. The ISS was calculated from the total antinociceptive effect produced by the combination after subtraction of the antinociceptive effect produced by the drug separately. Female rats received Ketorolac independently orally, Tramadol independently orally, or 24 different combinations of Ketorolac plus Tramadol. Material and methods.

For this study female rats of the genus Wistar [CrI (WI) BR] weighing 180-200 g were used.

The feeding was maintained 12 hours before the experiments with free access to water. All the procedures of the experiment followed the recommendations of the Committee for Research and Ethical

Issues of the International Association for the Study of Pain (Covino et al., 1980) and the Guidelines on Ethical Standars for Investigations of Experimental

Pain in Animáis (Zimmermann, 1983), and were carried out according to a protocol approved by the Animal

Local Ethics Committee The number of animals in the experiment was kept to a minimum, and the animals were kept in a room with climate and light control with a 12-hour light / dark cycle.

Medicines .

Uric acid was suspended in mineral oil; Ketorolac tromethamine, Tramadol Hydrochloride and Indomethacin were dissolved in carboxymethylcellulose and administered orally.

Measurement of antinociceptive activity. The antinociceptive activity was determined using the PIFIR model described in detail (López-Muñoz et al., 1993). The animals were anesthetized with ether in chamber (Pirex glass dryer saturated with ether vapor). Nociception was induced by an intra-articular injection (ia) of 0.05 inL. of uric acid suspended in mineral oil in the knee joint of the right hind leg. The suspension was prepared by mixing 3.0 g of uric acid with 10 mL. of mineral oil in a glass mortar with pistil (Pyrex). Intra-articular injection was carried out through the patellar ligament using a 1 mL glass syringe.

(Beckton Dickinson LTA, Brazil) with 24 mm needle. Immediately afterwards, an electrode was implanted to the plantar surface of each posterior claw between the plantar cushions. The rats were allowed to recover from anesthesia and then placed in a stainless steel cylinder which was rotated at a rate of 4 rpm, forcing the rats to walk for periods of 2 minutes every 30 minutes for 6.5 hours. A training period was not necessary because the rats learned it in the first minute. The time of Contact between each electrode implanted in the rat member and the cylinder was recorded. After uric acid injection, the rats progressively developed dysfunction of the damaged limb. The contact time of the damaged limb reached a value of zero after 2.5 hours of uric acid injection; at this time, Ketorolac and Tramadol were administered alone or in combination. This time was considered as zero time for measures of antinociceptive effects; These effects were measured every 30 minutes for the next 4 hours. This allowed to determine the course of the antinociceptive effects in the same animal. Antinociception was considered as the recovery of contact time. The data are expressed as percentage functionality index (IF%; that is, the contact time of the injected leg divided by the contact time of the left leg, control, multiplied by 100). For the purpose of this study, inducing nociception in experimental animals was inevitable. However, care was taken to avoid unnecessary suffering. All experiments were performed between 7:00 am and 2:00 pm. Study design.

The antinociceptive effects produced by Ketorolac and Tramadol administered either independently or in combination were studied. First, each dose of Ketorolac (0.18, 0.32, 0.56, 1.0, 1.78, 3.16 or 5.62 mg / kg) or Tramadol (3.16, 5.62, 10.0, 17.78, 31.62, 56.23 or 100.0 mg / kg) was given to six animals to obtain the corresponding dose - response curves and the doses of Ketorolac (0.10, 0.18, 0.32, 0.56, 1.0 or 1.78 mg / kg) and Tramadol (3.16, 5.62, 10.0 or 17.78 mg / kg) were then combined to analyze the possible synergistic interactions (24 combinations in total). At the end of the study the rats were sacrificed. Measurements of gastrointestinal effects.

Female rats of the Wistar genus (150-180 g of body weight) were fasted 24 hours before the experiment. They were given indomethacin (20 mg / kg) to cause 100% gastric ulcer (Lee et al., 1971; Déciga-Campos et al., 2003) were given orally Ketorolac (1.0 mg / kg), Tramadol ( 17.8 mg / kg), vehicle (0.5% carboxymethylcellulose) and the combination of Ketorolac plus Tramadol (1.0 and 17.8 mg / kg, respectively) at the same time and to the five groups (of six rats each). Around 2.5 hours later, all groups received a second administration of the same doses. Stomachs were examined 5 hours after the first treatment as follows: the animals were sacrificed and the stomach was removed, which was opened along the lower curvature, gently rinsed with formalin (2%) and It was examined. The severity of gastric lesions induced with medication was calculated as the ratio of the number of injuries (stomach ulcer or erosion) caused by the treatment provided and the number of injuries caused by indomethacin

(100%) This was considered to reflect the adverse effects induced by the medication. The sum of the area of all ulcers in each animal's body was calculated and served as an ulcerative index. The percentage of gastric lesions was calculated as follows:% of gastric lesion = (IUM / IUI) x 100 where IUM is the Ulcerative index of the drug under test (mm ² ) and IUI is the Ulcerative index of the Indomethacin tested ( mm ² ). Data presentation and statistical evaluation.

The study data, tables and figures are expressed as IF%. The curves for the IF% vs. time were made for each treatment and the corresponding time course was obtained. The antinociception was estimated as the recovery of the IF%. The accumulated antinociceptive effect during the entire observation period (4 hours) was determined as the area under the curve (ABC) of the course of time to obtain the dose-response curve and to analyze the total antinociceptive effect obtained by the analgesic agent already either alone or in combination.

The synergism between Ketorolac and Tramadol was calculated with the analysis of the Surface of the Synergistic Interaction (SIS) and with the Isobolographic Method (Tallarida et al., 1989). The ABC was calculated for each combination of the medications and for each of the components. On the basis of the addition of the individual pharmacological effects (Seegers et al., 1981), an ABC equivalent to the sum was expected. If the sum of the corresponding individual ABCs was higher than the theoretical sum, the result was considered potentiation: if it was similar to the theoretical sum it was considered to show additive antinociceptive effects. The ABC was obtained by the trapezoidal rule (Rowland and Trozer, 1989). All values for each treatment are average ± SEM, for six animals. The ABC values for the drug combinations were compared with the expected values using the Student test. The ABC values obtained from the antinociceptive effects produced by Ketorolac or Tramadol

(independently tested) were compared with the ABC values obtained from the corresponding combination by analysis of variance (ANOVA) and the test of

Dunnett The gastrointestinal side effects caused by Ketorolac or Tramadol (tested either separately or in combination) were compared with the gastrointestinal effects obtained from indomethacin by Dunnett's test. P <0.05 was considered statistically significant. The doses that caused 50% of the maximum possible effect (SD ₅₀ ) of each drug were calculated by performing a linear regression analysis of the linear portion of the dose - response curves. The isobologram is constructed using ED ₅₀ when drugs were administered independently or in combination. To execute the isobolographic analyzes, Ketorolac and Tramadol were given in combination as fixed rates of the effective dose DE ₅₀ for each drug (Ketorolac: Tramadol = 1: 1). The DE ₅₀ values (± SEM) for Ketorolac and Tramadol were delineated on the x- and y- axes, respectively and the theoretical additive point was calculated according to Tallarida et al., (1989). The DE ₅₀ value of the total dose of the combination was calculated from the dose-response curve of the combined drugs. The statistical significance between the theoretical additive point and the experimental value DE ₅₀ was assessed using the Student test. The experimental figure DE ₅₀ significantly lower than the theoretical addition DE ₅₀ (P <0.05) was considered to indicate synergistic interaction between Ketorolac and Tramadol. Results Effect of uric acid and vegetables. Uric acid induced a complete dysfunction of the right hind leg corresponding to an IF% value of zero in 2.5 hours. This dysfunction was maintained throughout the experimental period that lasted 4 hours. The rats that received vehicle (0.5% carboxymethyl cellulose) showed no significant recovery of IF% during the observation period. The doses of Ketorolac (0.18 - 5.62 mg / kg) and Tramadol (3.16 - 56.23 mg / kg) did not affect the walking ability of rats treated with vehicle (data not shown). Tramadol at 100 mg / kg, produced side effects in 50% of animals, sedation, euphoria, dizziness and effects on the ability of rats to walk.

Antinociceptive effects of individually tested drugs.

Figure 1 shows the dose-response curves for Ketorolac and Tramadol. Both drugs increased the dose-dependent ABC but showed different efficacy (eg, Ketorolac produced maximum efficacy). Therefore, Ketorolac (2.16 mg / kg) showed a high antinociceptive efficacy of 295.8 ± 14.9 au compared to Tramadol (56.23 mg / kg) which showed an antinociceptive activity of 207.7 ± 24.7 au. The ED ₅₀ values for the drugs indicate that there were significant differences in their antinociceptive potencies: Ketorolac (ED ₅₀ = 0.86 ± 0.10 mg / kg) It was more potent than Tramadol (ED ₅₀ = 44.29 ± 0.06 mg / kg). There were no adverse effects with the doses used. The antinociceptive effects shown by Tramadol at 100 mg / kg (236.7 ± 11.0 au) are not included in Figure 1 because it caused side effects in rats.

Antinociceptive effects of drug combinations.

Figures 2 to 4 describe the antinociceptive effect of the 24 combinations shown on three-dimensional graphs. These were constructed using the average of six animals for each dose administered either independently or in combination. The maximum antinociceptive effect that can be obtained from the various combinations of ketorolac

+ Tramadol (1.78 + 17.78 mg / kg, respectively; see Fig. 2) was 372.7 ± 15.6 au.

Statistical analysis of the data in Figure 2 indicate an interaction between Ketorolac and Tramadol (P <0.05) while there were no side effects of the combination tested.

Figure 3 was produced in order to discern between additive effects and potentiation effects. This The graph was calculated from the total antinociceptive effect produced by the combinations after subtraction of the antinociceptive effect produced by each independently administered component. Results greater than level "0" were considered to indicate potentiation, while those of level "0" were considered addition. Although this type of mapping allows observation of antagonistic antinociceptive effects, these were not obtained in the present study. Similarly, 14 combinations of Ketorolac + Tramadol produced antinociceptive effects and 10 produced potentiation with 95% reliability limits (P <0.05) (fig. 3). These combinations were: 17.78 mg / kg of Tramadol with either 0.18, 0.32 or 0.56 mg / kg Ketorolac; 10.0 mg / kg Tramadol with either 0.18, 0.32, 0.56 or 1.78 mg / kg Ketorolac; 5.62 mg / kg of Tramadol with either 0.32 or 0.56 mg / kg of Ketorolac and 3.16 mg / kg of Tramadol with 0.32 mg / kg of Ketorolac. In order to obtain the surface of the synergistic interactions for the Ketorolac + Tramadol combinations, all the interaction points of Fig. 3 were unified in one plane. The result is the synergistic interaction surface of these Analgesic medications shown in Figure 4. Using this graph, it is easy to visualize the drug interactions of Ketorolac + Tramadol (ie, addition or potentiation). For example, 10 combinations of Ketorolac + Tramadol showed different degrees of potentiation of the antinociceptive effects, but 2 combinations of Ketorolac + Tramadol showed high potentiation effects (0.32 ± 10 and 0.56 + 10 mg / kg, respectively) (see Table 1). Tramadol at the dose of 10.0 mg / kg provided an ABC of 22.5 ± 9.3 au and Ketorolac at the dose of 0.32 mg / kg showed an ABC of 65.0 ± 9.6 au; however, the combination of Ketorolac + Tramadol (10 + 0.32 mg / kg) allowed an AUC of 233.5 ± 25.8 au, which is greater than the expected ABC resulting from the sum of the individual values (ie, 87.5 au) (P <0.Q01). The analysis of the E _max of the corresponding time course curves showed an increase in the values obtained from the combinations (86.6 + 6.3%) which was higher than the corresponding values (Ketorolac 33.7 ± 8.7% and Tramadol 17.1 ± 9.1 %) obtained from the arithmetic sum (50.8%). Other examples of potentiation of Ketorolac + Tramadol are shown in table 1.

The antinociceptive effects obtained by the combinations that produced the maximum antinociceptive effect (1.78 mg / kg of Ketorolac + 17.78 mg / kg of Tramadol) and the combination that produced higher potentiation (0.56 mg / kg of Ketorolac + 10.0 mg / kg of Tramadol ) is shown in Fig. 5. As can be seen in Fig. 5A, the antinociception produced by Ketorolac + Tramadol (1.78 + 17.78 mg / kg) represented the maximum antinociceptive effect (which represents a total recovery) obtained with 372.7 ± 15.6 au, while Ketorolac administered independently (1.78 mg / kg) showed an ABC of 279.0 ± 15.5 au, and Tramadol administered independently (17.78 mg / kg) produced 58.2 ± 23.7 au, only. This result was important considering that the maximum dose of ketorolac used (3.16 mg / kg) produced less antinociceptive effect: 295.8 + 14.9 au. The combination described in Fig. 5B (0.56 mg / kg Ketorolac + 10.0 mg / kg Tramadol) only represents a combination that produced maximum potentiation of the antinociceptive effect (169.4% more ABC or full antinociceptive effect than the sum of individual ABCs); likewise, both the time course and the ABC obtained with this combination were higher (P <0.001) than the respective values obtained with the sum of the individual agents

(121.2 au). The antinociception produced by

Ketorolac / Tramadol (0.56 + 10.0 mg / kg) was 290.6 ±

27.7 au, while Ketorolac administered independently (0.56 mg / kg) showed an ABC of 98.7 + 15.5 au and Tramadol administered independently (10.0 mg / kg) produced 22.5 ± 9.3 au only. A significant antinociceptive effect was obtained with the combination throughout the observation period (4 hours). Another approach to investigate the synergistic interaction between the two selected analgesic drugs is the isobolographic method, Tallarida et al., 1989. An isobologram is shown in Fig. 6 in which the antinociceptive interaction of Ketorolac and Tramadol can be seen in the model of functional disability induced by pain in rats. The horizontal and vertical bars indicate the SEM The oblique line between the "x -" and "y -" axes is the additive theoretical line. The point in the middle of this line is the theoretical additive point calculated from the separated DE values. The experimental point is located far below the additive line, indicating an additive synergism (P <0.05). Measurement of gastrointestinal side effects.

The administration of Tramadol did not produce ulcers or erosions. Its adverse effects were similar to those of the vehicle. However, Ketorolac generated a lower area of ulcers (13.7 ± 2.7 mm ² ) and fewer erosions (15.0 ± 4.9) than Indomethacin

(P <0.05), which was considered as the most harmful component in terms of number and severity of stomach injuries (ie, ulcers and erosions) (100%). The combination of Ketorolac + Tramadol generated fewer ulcers (16.9 + 6.9 mm ² ) and fewer erosions (5.0 ± 1.4) than Indomethacin (P <0.05). Interestingly, the combination of Ketorolac + Tramadol reduced the generation of erosions (P <0.05) and the ulcerations were similar to those produced by the independently administered Ketorolac (Table 2). Table 2.

Comparison of gastrointestinal side effects expressed as a percentage of gastric lesion caused by Indomethacin (20 mg / kg), Ketorolac (1 mg / kg), Tramadol (17.8 mg / kg) and the combination of Ketorolac and Tramadol (1 and 1.78 mg / kg, respectively).

Treatment No. of erosions Ulcers ^a (mm) Gastric lesion (%)

Vehicle 0 0 0

Indomethacin 30.0 + 3.9 51.6 + 3.4 100

Ketorolac 15.0 + 4.9 ° 13.7 ± 2.7 ° 26.6

Tramadol 0 0 0

Ketorolac / Tramadol 5.0 + 1.4 ° 16.9 + 6.9 ° 32.8

Sum of the area of all ulcers. b (index of ulcers in drug tests / index of ulcers in indomethacin tests) x 100, where the index of the area of all stomach ulcers. 0 ANOVA (Dunnet test), P <0.05 with respect to Indomethacin.

Ex emplo 2:

The bioavailability of two oral and one sublingual formulations was compared, after a single dose of 40 mg. + 100 mg of Ketorolac tromethamine / Tramadol hydrochloride, respectively, which were administered after a fast of at least 10 hours in two independent sessions, with an interval of one week of washing. Blood samples were taken for up to 24 hours after medication administration. Plasma concentrations of both ketorolac were determined tromethamine as Tramadol hydrochloride, using a high performance liquid chromatography method. The plasma concentration profiles with respect to time demonstrated a similar behavior, obtaining the pharmacokinetic parameters illustrated below.

Pharmacokinetic parameters for Ketorolac tromethamine.

Cmax (ng / mL) ABC 0 → QQ (hr * ng / ml_) Tmax (hr.)

Shape Shape Shape

chap. Tab. chap. Tab. chap. Tab.

Mean 8920.79 7180.27 35566.97 35566.97 0.79 0.88

SD 2719.20 2091.23 9928.89 9928.89 0.50 0.50

CV% 30.5 29.1 27.9 27.9 63.9 57.3

Geometric mean 8516.77 6867.32 34311.24 34311.24 0.69 0.77

Pharmacokinetic parameters for Tramadol Hydrochloride.

Cmax (ng / mL) ABC 0 → QQ (hr ^* ng / mL) Tmax (hr.)

Shape Shape Shape

chap. Tab. chap. Tab. chap. Tab.

Mean 412,635 562,855 3345. 732 4145 .427 1,462 1,106

SD 132,632 174,889 1964. 353 1757 .071 0.780 0.867

CV% 32.1 31.1 58.7 42.4 53.4 78.4

_Geometric mean 388.995 534.449 2924.952 3829.342 1.233 0.889

To determine the existence no of the

Bioavailability between both drugs, the log transformation of the data was performed and the analyzed using the WinNonlinTM statistical package.

The confidence intervals proposed by the FDA for semi-logarithmic data in the determination of the Bioequivalence of two products are 80 to 125%. The classic and Westlake confidence intervals obtained for Cmax, ABC 0-t and ABC 0 - »∞ were:

Statistical analysis of the pharmacokinetic parameters of Ketorolac tromethamine.

Dependent Un its Difference Ratio (% Ref) C190Lower C190Upper WL90Lower WL90Upper Ahpval Power

Ln (Cmax) ng / mL 0 2153 72 78 109 61 140 32 63 61 136 39 0 4570 0 9101

LnAUCINF ng / mL -0 0457 95 53 89 96 101 45 91 20 108 80 0 0000 0 9999

Statistical analysis of the pharmacokinetic parameters of Tramadol hydrochloride.

Dependent Units Difference Ratio (% Ref) C190Lower C190Upper WL90Lower WLΘOUpper Ahpval Power

LogiOCmax ng / mL -0 3177 124 02 6429 8240 66 15 133 85 0 8975 0 9075

LogABC hrng / mL -0 2694 76 38 70 26 83 04 71 62 128 38 0 8235 0 9957

The Imax quotient values (Tab. / Cap.) Is 124.02 which implies that the tablet is absorbed faster by 24% and so that it presents a bioequivalence between the two pharmaceutical forms, the calculated intervals (109.61 to 140.32) they should be between 80 and 120%, which turned out to be no true for Imax, this implies that the tablet has a greater bioavailability in terms of absorption speed and possibly has a faster therapeutic effect. However, for ABC - »oo which represents the amount absorbed does not happen the same and the two pharmaceutical forms can be considered bioequivalent.

Conclusion. The formulations of the combination Ketorolac tromethamine 10 mg. and Tramadol hydrochloride 25 mg. in sublingual tablets they have a higher bioavailability regarding the rate of absorption, but they are bioequivalent in the amount absorbed compared to the combination in capsules.

Claims

NOVELTY OF THE INVENTION. Having described the present invention, it is considered as a novelty and, therefore, what is contained in the following is claimed as property: CLAIMS

1.- Pharmaceutical composition composed of the synergistic combination of a non-steroidal anti-inflammatory agent and an opioid analgesic agent, characterized in that the non-steroidal anti-inflammatory agent is the active substance: Ketorolac tromethamine and the opioid analgesic agent is the active substance: Tramadol hydrochloride, same which are formulated in a single dosage unit in the form of a sublingual tablet, which has greater bioavailability, its therapeutic action is more effective and manifests less side effects.

2. - Pharmaceutical composition according to claim 1, characterized in that the active substance: Ketorolac tromethamine is present in the formulation in a concentration range of 0.0010 a

0.10000 g. per dose unit.

3. - Pharmaceutical composition according to claim 1, characterized in that the active ingredient: Tramadol hydrochloride is present in the formulation in a concentration range of 0.0010 to 0.20000 g. per dose unit.

4. - Pharmaceutical composition according to claims 1 to 3, characterized in that it is formulated in a single dosage unit, in which a synergy occurs such that results in the incorporation of lower concentrations of each of the active ingredients, same that are formulated to be administered orally in the form of a sublingual tablet.

5. - The use of the pharmaceutical composition according to claims 1 to 4, characterized in that it is indicated for the relief and / or treatment of moderate to severe intensity pain caused by: headache, dental discomfort, sports injuries, surgeries, as well as for chronic conditions, such as: cancer or joints, in addition to other conditions that cause pain.